Management of patients with brain metastases receiving trastuzumab treatment for metastatic breast cancer

Background: With the more effective control of visceral metastases in patients with metastatic breast cancer (MBC), an increasing number of patients face brain metastases (BM). The aim of this retrospective analysis was to investigate the incidence and factors affecting the prognosis of patients with BM under trastuzumab treatment for MBC. Patients and Methods: A total of 75 HER2positive patients treated with trastuzumab for MBC were included. Results are discussed in the context of the current literature. Results: Patients who developed BM (n = 29) had longer median progression-free survival (PFS) during first-line chemotherapy and longer overall survival (OS) after diagnosis of MBC than 46 patients without BM (PFS: 27 vs. 14 months, p = 0.039; OS: 46 vs. 18 months, p = 0.067). Median survival of patients with continuation of trastuzumab after diagnosis of BM was longer than survival of patients with discontinuation of trastuzumab treatment after BM (18 vs. 3 months, p = 0.006). Survival of patients who were treated with surgery and radiotherapy for BM was better compared with radiotherapy alone (9 vs. 5 months, p = not significant) or best supportive care (9 vs. 2 months, p = 0.049). Conclusions: Continuation of trastuzumab treatment as well as resection of BM seem to give further benefit in the treatment of patients with HER2-overexpressing MBC.     

ERG oncogene modulates prostaglandin signaling in prostate cancer cells

Androgen dependent induction of the ETS related gene (ERG) expression in more than half of all prostate cancers results from gene fusions involving regulatory sequence of androgen regulated genes (i.e. TMPRSS2, SLC45A3 and NDRG1) and protein coding sequence of the ERG. Emerging studies in experimental models underscore the functions of ERG in prostate tumorigenesis. However, biological and biochemical functions of ERG in prostate cancer (CaP) remain to be elucidated. This study suggests that ERG activation plays a role in prostaglandin signaling because knockdown of ERG expression in TMPRSS2-ERG fusion containing CaP cells leads to altered levels of the 15-hydroxy-prostaglandin dehydrogenase (HPGD), a tumor suppressor and prostaglandin catabolizing enzyme, and prostaglandin E2 (PGE2) . We demonstrate that HPGD expression is regulated by the binding of the ERG protein to the core promoter of this gene. Moreover, prostaglandin E2 dependent cell growth and urokinase-type plasminogen activator (uPA) expression are also affected by ERG knockdown. Together, these data imply that the ERG oncoprotein in CaP cells positively influence prostaglandin mediated signaling, which may contribute to tumor progression.     

Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma

In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain “prognostic groups”. However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0–124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series.     

Role of HYAL1 expression in primary breast cancer in the formation of brain metastases

Background

The incidence of brain metastases in breast cancer patients has increased in the last years. However, the knowledge about tumor cell invasion in the brain is still very limited. Based on our recent study on cDNA microarray data of breast cancer patients, we hypothesized that two enzymes involved in the hyaluronan metabolism, namely, hyaluronan synthase 2 (HAS2) and hyaluronidase 1 (HYAL1) are associated with brain metastases formation.

Methods

Protein expression levels of hyaluronan, HAS2, and HYAL1 were analyzed in primary breast cancer, and metastatic tissue samples from different localizations (brain, bone, skin, liver, and lung) were included in four different cohorts by immunohistochemistry. Correlations of expression levels with clinical and pathological parameters were performed within the individual cohorts.

Results

Higher HYAL1 expression was detected among primary tumors from patients with subsequent brain metastases compared with those without brain metastases (p = 0.011). Interestingly, brain metastatic tissue showed a significantly reduced HYAL1 expression compared with the corresponding primary tumor (p = 0.003). HYAL1 expression in brain metastases was also significantly lower than in skin, liver, and lung metastases. Further, hyaluronan staining in brain metastases was mainly located on the surface of the tumor cells, whereas in all other metastatic sites hyaluronan was only detected in the extracellular matrix. We could not show an association of HAS2 with the formation of brain metastases.

Conclusions

In conclusion, our results suggest that the enzyme HYAL1 plays a role in tumor dissemination and brain-specific colonization, rather than in subsequent metastatic out-growth.

     

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

Background

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.

Positive effects of a computerised working memory and executive function training on sentence comprehension in aphasia

Aphasia, the language disorder following brain damage, is frequently accompanied by deficits of working memory (WM) and executive functions (EFs). Recent studies suggest that WM, together with certain EFs, can play a role in sentence comprehension in individuals with aphasia (IWA), and that WM can be enhanced with intensive practice. Our aim was to investigate whether a combined WM and EF training improves the understanding of spoken sentences in IWA. We used a pre–post-test case control design. Three individuals with chronic aphasia practised an adaptive training task (a modified n-back task) three to four times a week for a month. Their performance was assessed before and after the training on outcome measures related to WM and spoken sentence comprehension. One participant showed significant improvement on the training task, another showed a tendency for improvement, and both of them improved significantly in spoken sentence comprehension. The third participant did not improve on the training task, however, she showed improvement on one measure of spoken sentence comprehension. Compared to controls, two individuals improved at least in one condition of the WM outcome measures. Thus, our results suggest that a combined WM and EF training can be beneficial for IWA.     

Experiences with a specific screening instrument to identify psychosocial support needs in breast cancer patients

Objective

In order to determine the need for professional psychosocial support in breast cancer patients, we used the physician-administered Basic Documentation for Psycho-Oncology (PO-Bado), which is an expert rating scale containing 12 items belonging to somatic and psychological problems. Furthermore, we investigated sociodemographic and medical predictors of somatic and psychological distress and need for psychosocial support.

Study design

From 2/2005 to 09/2007, n = 333 consecutive patients with breast cancer were included in the study. The majority of the patients suffered from early-stage breast cancer. The mean age of the participants was 59.9 years (SD = 12.6, range 24–92). Two physicians rated patients’ psychosocial distress and evaluated their need for psychosocial support according to the PO-Bado guidelines.

Results

Exhaustion/tiredness was the item rated highest in the physical distress dimension. In the psychological distress dimension, the items anxiety/worries/tension and grief/despondency/depression obtained the highest mean. Younger age and a history of psychiatric/psychotherapeutic treatment in the past were associated with higher current distress. Women who planned to undergo mastectomy were rated as showing more somatic distress than women for whom breast conserving therapy was planned, but the two groups did not differ with regard to psychological distress. Objective cancer-related variables (tumour size and grading) were not associated with distress. Need for professional psychosocial support was seen in 23% of the patients. Previous psychiatric/psychotherapeutic treatment was the only variable associated with current need for psychosocial support. Forty-six percent of the patients with need for psychosocial support accepted the counselling offered.

Conclusions

The structured assessment of breast cancer patients’ psychosocial distress with the interviewer-administered PO-Bado assists the physician to arrive at a detailed expert evaluation. This might help to improve the psychosocial care of breast cancer patients.     

Paediatric multiple sclerosis and acute disseminated encephalomyelitis in Germany: results of a nationwide survey

The aim of this study was to evaluate the incidence of paediatric multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) in Germany. In a prospective nationwide survey carried out between 1997 and 1999, all registered new cases of paediatric MS and ADEM with an onset before the age of 16 years were evaluated using a standardised questionnaire. A total of 132 patients with suspected or definite MS and 28 patients with an assumed diagnosis of ADEM were reported. Among these, 82% of the MS patients were 10 years of age or older, as opposed to 18% in the ADEM-cohort. The female-to-male ratio was 1.2:1 in the MS-cohort and 0.8:1 in the ADEM-cohort. Manifestation was polysymptomatic in 67% of the MS patients compared to 86% of the ADEM patients. The most frequent primary symptoms in the MS-cohort were cerebellar (44%), sensory (39%) or visual (36%), followed by brainstem (30%), pyramidal (29%) and cerebromental (22%) complaints. Conclusion: The incidence of paediatric MS in Germany is more than fourfold higher than that of paediatric ADEM; in addition, it shows a strikingly different age-distribution. With an estimated minimum of 50 new cases per year, the incidence of paediatric MS in Germany is much more frequent than previously believed. This paper is dedicated to Prof. Dr. Helmut Bauer for his continuing encouragement and support of research in paediatric MS.     

Consensus Recommendations of the German Consortium for Hereditary Breast and Ovarian Cancer

BackgroundThe German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multigene panel (TruRisk®) for the analysis of risk genes for familial breast and ovarian cancer.SummaryAn interdisciplinary team of experts from the GC-HBOC has evaluated the available data on risk modification in the presence of pathogenic mutations in these genes based on a structured literature search and through a formal consensus process.Key MessagesThe goal of this work is to better assess individual disease risk and, on this basis, to derive clinical recommendations for patient counseling and care at the centers of the GC-HBOC from the initial consultation prior to genetic testing to the use of individual risk-adapted preventive/therapeutic measures.     

Update Breast Cancer 2022 Part 2 – Advanced Stage Breast Cancer

For patients with advanced breast cancer, several novel therapies have emerged in recent years, including CDK4/6 inhibitors, immune checkpoint inhibitors, PARP inhibitors, alpelisib, tucatinib and trastuzumab-deruxtecan, and sacituzumab-govitecan, which have transformed and expanded the therapeutic landscape for patients with advanced breast cancer. Some of these substances have now been approved for use in the early stages of the disease, or are expected to be approved in the near future, so the therapeutic landscape will change once again. Therefore, current scientific efforts are focused on the introduction of new substances and understanding their mechanisms of progression and efficacy. This review summarizes recent developments with reference to recent publications and conferences. Findings on the treatment of patients with HER2-positive breast cancer and brain metastases are presented, as are a number of studies looking at biomarkers in patients with HER2-negative, hormone receptor-positive breast cancer. In particular, the introduction of oral selective estrogen receptor degraders provides new opportunities to establish biomarker-based therapy. Molecular diagnostics is establishing itself as a diagnostic marker and parameter of progression.Key words: breast cancer, metastatic, biomarker, PD-L1, ADC